This is a resubmission of the previously submitted proposal investigating the regulation of luminal breast cancer stem cells by HER2. We have addressed the previous critiques by adding an investigator with expertise in bone biology, Evan Keller, and a biostatistician, Kelley Kadwell. In addition, we have added new preliminary data and refined the research plan. The development of HER2 targeting agents represents one of the greatest advances in the therapy of breast cancer. Although the use of HER2 targeting agents such as trastuzumab has been limited to breast cancers with HER2 gene amplification, recent retrospective analyses of adjuvant trastuzumab studies suggests that a much wider group of breast cancer patients may benefit from this therapy. We propose that the biological basis for these surprising clinical findings relates to the "cancer stem cell (CSC)" model. We hypothesize that HER2 is selectively expressed in CSC populations in luminal breast cancers where it plays a major role in the regulation of CSC self-renewal. Furthermore, we hypothesize that the bone microenvironment induces HER2 expression expanding the CSC population in luminal breast cancer bone metastasis. This is mediated by RANKL-RANK-NF?B signaling in a process independent of HER2 gene amplification. We propose that the clinical efficacy of adjuvant trastuzumab in women whose breast cancers do not display HER2 gene amplification (HER2-negative) is due to the effective targeting of CSCs in micrometastasis in these patients. We propose to utilize established breast cancer cell lines, primary human xenografts and primary and metastatic breast cancer tissues from patients to directly test these hypothesies. These studies directly challenge the current clinical paradigm that only the 20% of women with HER2 amplified breast cancers benefit from adjuvant HER2 blockade which, if confirmed would have significant clinical implicaitons. These studies provide a strong biological rationale for the current intergroup trial NSABP-B47, a phase III study designed to determine whether adjuvant trastuzumab benefits women with "HER2-negative" tumors. Furthermore, the proposed studies have broader implications for the development of adjuvant cancer therapies. If CSCs mediate tumor recurrence, then effective adjuvant therapies will need to successfully target this cell population.
Although the development of HER2 targeting agents represents one of the greatest clinical advances in breast cancer treatment, current guidelines limit this treatment to the 20% of breast cancers that display HER2 gene amplification. Based on the cancer stem cell hypothesis, we propose that the clinical efficacy of HER2 blockade in the adjuvant setting may have clinical utility in a far larger population of breast cancer patients. If HER2 blockade reduces tumor recurrence in this wider patient populations, then this therapy has the potential to significantly reduce breast cancer mortality. In addition, these studies have broader implications for the development of more effective adjuvant cancer therapies.
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