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The State of the Fight: Breast Cancer

by Jose Silva, Ph.D.

The State of the Fight: Breast Cancer
José M. Silva, Ph.D., is assistant professor of pathology at the Institute for Cancer Genetics at Columbia University Medical Center. Silva was awarded a SU2C Innovative Research Grant for his project, "Genetic Approaches for the Next Generation of Breast Cancer-Tailored Therapies."

The mammary gland contains several cell types: the epithelium, the adipose, the connective and the lymphatic tissue. Breast cancer begins in the mammary epithelium that forms the glands and the ducts. Breast tumors represent more than 30 percent of all newly diagnosed malignancies in women, far more than other tumor types. It is estimated that one out of eight women will suffer from breast cancer during her lifetime. One of the major reasons for such a high incidence resides in the strong dynamics of the mammary gland. During puberty, the development of the mammary gland leads to widespread branching morphogenesis of the epithelium. After puberty, hormones released by the ovary during the menstrual cycles induce extensive remodeling of the mammary epithelium, which leads to continuous cycles of expansion and involution. These cycles are supported by cell proliferation and death. Mutagenesis of the cell genome is intimately linked to DNA replication that occurs during cell division. The continuous proliferative cycles of the mammary gland create multiple opportunities for DNA mutations to accumulate. Thus, it is not surprising that breast cancer incidence increases with age. The average age of a breast cancer diagnosis is 61 years old.

Fortunately, a breast cancer diagnosis is not a death sentence. After slowly increasing for many years, death rates started decreasing in the early 1990s. The major factor influencing prognosis is the stage of disease - that is, the extent or spread of the cancer. When the disease is confined to the breast and nearby lymph nodes, which is the case for the majority of patients with breast cancer, the five-, 10- and 15-year survival rates are 89 percent, 82 percent and 77 percent, respectively. Although the survival numbers are very good compared with other tumor types (i.e., lung or pancreas), management of metastatic disease is problematic. Once breast cancer has spread to other organs, patient survival sharply decreases to less than 20 percent within five years.

The overall decline in mortality has been attributed to improvements in early detection and treatments. With the widespread use of periodic mammography screening, tumors are frequently being detected while patients are still asymptomatic. Furthermore, the use of modern therapeutic protocols provides a comprehensive strategy to treat the disease both locally and systemically. Thus, although each patient will have a “personalized” treatment, on which she and her doctor decide, a standard treatment will most likely include neoadjuvant chemotherapy to shrink the tumor mass, followed by surgery to remove the remaining cancer. Then, the final steps will be breast irradiation to destroy cancer cells that were missed by the surgery and adjuvant chemotherapy to eliminate malignant cells that are potentially being disseminated through the body. Although novel targeted therapies are being included in the arsenal of the oncologist, traditional chemotherapy still forms the basis of treating high risk cancers. Chemotherapy regimens will normally include a combination of alkylating agents (i.e., Cyclophosphamide), anthracycline antibiotics(ea, Adriamycin), antimetabolites (i.e., 5-Fluorouracil), and taxanes (i.e., Taxol). These multidrug treatments have proven to be more effective than the use of single agents.

The characterization of the tumors at a molecular level has revealed that breast cancers can be divided into several distinct groups. Importantly, the identification of these molecular subtypes has set the basis for the development of targeted therapies for each specific group. Estrogen and progesterone are hormones produced mainly by the ovaries and promote the growth of many breast cancer cells. Women whose breast cancers test positive for estrogen and/or progesterone receptors can be given drugs that block the effects of these hormones, such as competitive antagonists (i.e., tamoxifen), or that inhibit estrogen production (i.e., aromatase inhibitors).

Approximately 25 percent of breast cancers overexpress the oncogene HER2/neu. HER2 is a cell membrane surface-bound receptor tyrosine kinase that is involved in signal transduction pathways leading to cell growth. These tumors tend to grow faster and are generally more likely to recur than tumors that do not overproduce HER2. Combining HER2 blockage by using the monoclonal antibody Trastuzumab (Herceptine) together with standard chemotherapy reduced the risk for recurrence and death in women with HER2-positive tumors. A third molecular subtype with clinical relevance is the triple negative. These tumors are characterized by the absence of both hormone and HER2 receptors. Consequently, these patients do not benefit from existing targeted therapies, leaving standard chemotherapy as the sole option.

Although breast cancers appear mainly in unrelated individuals (sporadic cancers), they may result from inherited mutations shared by relatives of the same family (familial cases). The most common of these mutations is BRCA1 and BRCA2, which accounts for between five and ten percent of breast cancers.

Importantly, the understanding of the molecular mechanism controlled by BRCA genes has led to the design of a new targeted therapeutic strategy. In cells that carry BRCA1 and BRCA2 mutations, one of the two major DNA repair mechanisms, known as homologous recombination, is nonfunctional. However, the other major repair method, known as base-excision repair (BER) can compensate for that loss. Inhibition of a key enzyme for BER, PARP-1, disables this pathway and leaves the tumor cells without a major source for DNA repair. This leads to cell death of the BRCA mutant cells while sparing normal cells. Although still in clinical trials, PARP-1 inhibition has emerged as one of the most exciting findings in breast cancer therapeutics in a long time.

The design of targeted therapies is dominated by what is called “oncogene addiction”. That is, cancer cells that upregulate some function become dependent on this alteration, and its inhibition compromises cancer cell viability. Normal cells, on the contrary, will be more permissive and will better tolerate the treatment. A clear example of this effect is seen with antihormonal and anti-HER2 therapies. However, as mentioned before, current therapies based on this effect fail to provide a long-term cure due to innate and acquired resistance.

My laboratory is addressing this issue by applying state-of-the-art strategies to identify genetic synthetic lethal interactions with common breast cancer alterations. During the process of transformation, multiple normal regulatory networks need to be rearranged to adapt to the tumorigenic state. As a consequence of this divergence, survival of cancer cells also depends on noncancerous genes that are essential to maintain tumor homeostasis. Interfering with these noncancerous dependencies will result in the cessation of the tumorigenic state. Importantly, the genetic alterations that different tumors accumulate define how the tumor’s network is reorganized and what functions are now essential for its survival.

The phenomenon that occurs when inhibition of a certain cellular function reduces the viability of a cancer cell that carries a specific alteration represents what is called a “genetic synthetic lethal interaction.” The idea is that genetic synthetic lethal interactions can be exploited to design targeted therapies against the specific cancer alterations that are present in each individual tumor. A good example of this phenomenon is the PARP-1 inhibition in BRCA1 or BRCA2 mutant tumors. Unfortunately, genetic synthetic lethal alterations cannot be easily predicted and needs to be discovered experimentally. My laboratory has pioneered the development of RNA interference genetic approaches to individually interrogate every gene in the human genome by loss-of-function studies to discover genetic synthetic lethal interactions with bona fide breast cancer genes.

Using this research strategy, we have recently identified a novel target for HER2-positive tumors that have stopped responding to chemotherapy and anti-HER2 therapy. Currently, we have started a second phase of preclinical studies to identify small molecule inhibitors that can be effectively used in the clinic. Additional studies for other breast cancer alterations are also on their way. Thanks to the outstanding support of the SU2C program, we hope to complete a research plan that will provide us with novel targets for more efficient and less harmful breast cancer therapies and that will impact the design of future generations of cancer treatments. Furthermore, our research illustrates a comprehensive and systematic strategy to discover novel tumor targets that can be applied to any other cancer type.

Our study would not be possible without the uniqueness of the SU2C grant. I am convinced that promoting and supporting novel ideas and the possibility to explore new concepts and technologies that deviate from traditional research can dramatically impact the way we understand and treat cancer.

Understanding the potential of these unconventional studies and supporting the most promising ones is not an easy task. Furthermore, the strong interaction between all the research groups supported by these awards provides us with a unique environment where novel and exciting results and ideas are discussed.

For those who are fighting breast cancer, I would like to reinforce the idea that a breast cancer diagnosis is not a death sentence. Multiple therapeutic options already exist (surgery, radiation, chemotherapy, antihormonal therapies, etc.), and novel promising options are on their way to the clinic (PARP-1, mTOR and PI3K inhibition among others). For those at risk for breast cancer, I urge you to get screened regularly and continue to do self-breast examinations. Early detection remains the best way to increase the chances of survival. I would be lying if I said that we will cure everybody. But as with everything in life, the only way to succeed is to never give up. We, as scientists and clinicians, are not giving up. Please keep fighting together with us.

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